1. Field of the Invention
This invention relates to penicilloyl-polylysine conjugates useful for eliciting cutaneous responses in persons having penicillin hypersensitivity and to processes for the manufacture of such compositions.
2. Discussion of the Prior Art
It is well known that significant proportions of the population are hypersensitive to penicillin. Individual allergic reactions to penicillin range from urticaria to acute anaphylactic shock, the latter which is frequently fatal. It is highly desirable, therefore, to provide means for readily identifying patients who may have penicillin allergy, and more particularly, a means to identify those patients who may become victims of anaphylactic shock.
Existing procedures for screening patients for allergic reactions to penicillin, however, are not entirely reliable. In addition, the skin tests heretofore employed have not been completely reliable.
Penicillin itself is unsatisfactory for skin testing for many reasons. For example, testing results are often times erratic. In addition, penicillin may sensitize the patient, it may produce shock, or it may not produce reactions to the degradation products of penicillin to which the patient may be hypersensitive.
It has been necessary, therefore, to discover other procedures, methods, compounds, and compositions that may indicate penicillin hypersensitivity. Consequently, many different materials have been investigated and significant amounts of research have been devoted to this problem. The many years of study and effort, however, have resulted in a wide variety of proposals.
One publication of reagents for skin testing by Levine and Fellner, Journal of Allergy, 36: 342, 1965 reported tests of certain conjugates of penicillin with polylysine on human patients with a history of penicillin hypersensitivity for the purpose of studying the relative effectiveness of the various conjugates: extent of conjugation, molecular size of the conjugate, and poly-L-lysine versus poly-D-lysine of a variety of molecular sizes were equally effective in eliciting skin reactions. Moreover, the conjugates made were water insoluble and were succinylated by reaction with succinic anhydride.
Levine, Journal of Med. Chem. 7: 675, 1964, disclosed the preparation of penicilloyl-polylysines, by the reaction of penicillin with aqueous solutions of polylysine. The reaction products were treated with succinic anhydride (succinylated) to make them soluble and the conjugates showed optical activity. Here it was concluded that the penicilloyl groups contained in the conjugates by the reported method of preparation was entirely, or predominately, .alpha.-diastereoisomers, which contrasted to the diastereoisomeric mixtures prepared from penicillenic acids. The optical rotations of the conjugate solutions corrected for the contribution of succinylated poly-L-lysine yielded [.alpha.].sub.D.sup.25 = + 0.96.degree. for 1 .times. 10.sup..sup.-2 M benzyl penicilloyl contained in a typical benzylpenicilloyl-poly-L-lysine (succinylated) conjugate. It was also reported that these particular .alpha. -diastereoisomers were at least as effective as are the diastereo-isomeric mixtures obtained from penicillenic acids.
Parker and Thiel, J. Lab. & Clin. Med. 62: 482, 1963, in a study comparing various penicilloyl-polylysines concluded that the benzylpenicilloyl-polylysines prepared from penicillin and penicillenic acid are generally equivalent as elicitors of cutaneous responses.